Our long-range goal is to understand the modifications that occur during the first steps of cancer versus normal tissue development. Despite decades of intensive research that led to the characterization of a sequence of genetic abnormalities in pancreatic ductal adenocarcima (PDAC), the initiating events as well as the cellular type(s) where these occur remain elusive. Yet the reason for the high mortality rate is the late diagnosis blamed onto the lack of means of detection of the cancer at early stages. We plan to design an animal model of PDAC that will allow the study of the initiating events and the identification of the cellular compartment that is affected. Our main hypothesis is that a restricted pancreatic cell population is the compartment where the initiating transformation events occur and this finally leads to PDAC. The major goal of this research proposal is to elucidate, using genetically engineered mice, if the activation of an oncogene in this cell population is sufficient for initiating PDAC. The incidence of PDAC peaks in the fifth decade of life, and remains an important cause of cancer death in subsequent years. This would suggest that the genetic lesion(s) occurs late in life. To generate an animal model that reproduces faithfully the early events of human cancer, we have design a second mouse model of PDAC that will allow for the activation of the oncogenic mutation in this cell population specifically in adulthood. Finally, we plan to characterize the cell population for a better understanding of its specific response to oncogenic events. The rationale that underlies the proposed research is that once a relevant PDAC animal model is engineered, it will be possible to define early markers of pancreatic cancer for early diagnosis as well as develop new therapeutic approaches. Pancreatic ductal adenocarcima (PDAC) is among the most lethal human cancers, the main reason being the late diagnosis blamed onto the lack of means of detection of the cancer at early stages. The identification of the molecular and cellular pathways important in PDAC initiation and progression is essential for the development of effective approaches of prevention, early detection and therapy. [unreadable] [unreadable] [unreadable]